Method for achieving tissue changes in bone or bone-derived tissue

ABSTRACT

A method of achieving tissue changes in bone or bone-derived organic tissue, in which method bone or bone-derived organic tissue is provided, an interfacing agent is applied to the bone or bone-derived organic tissue, and electromagnetic energy is applied to the interfacing agent. The interfacing agent can include collagen, preferably bone-derived collagen, and a therapeutic agent. In a related embodiment, a method of treating bone tissue is provided wherein a bioactive interfacing agent is placed between the bone segments of the bone tissue to be treated.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. App. No. 09/885,749now U.S. Pat. No. 6,547,794, now filed Jun. 19, 2001 entitled Methodsfor Fusing Bone During Endoscopy Procedures, issued on Apr. 15, 2003,and the specification thereof is incorporated herein by reference. Thisapplication and U.S. Pat. No. 6,547,794 claim the benefit of the filingof U.S. Provisional Patent Application Ser. No. 60/226,370, entitledMethod For Fusing Bone During Endoscopy Procedures, filed on Aug. 18,2000, and of U.S. Provisional Patent Application Ser. No. 60/272,955,entitled Method For Fusing Bone During Endoscopy Procedures, filed onMar. 2, 2001, and the specifications thereof are incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention (Technical Field)

The present invention is directed to the in vivo fusing and/or weldingof bone in a fluid medium, particularly useful in endoscopy procedures.

2. Background Art

Note that the following discussion refers to a number of publications byauthor(s) and year of publication, and that due to recent publicationdates certain publications are not to be considered as prior artvis-a-vis the present invention. Discussion of such publications hereinis given for more complete background and is not to be construed as anadmission that such publications are prior art for patentabilitydetermination purposes.

The medical arts do not at present provide a consistent and usefulprocedure for fusing or welding bone in vivo in a fluid medium, such asduring endoscopy procedures. Further, since all in vivo healing andcellular processes occur in a fluid medium and are dependant upon tissuehydration, the prior art does not provide for fusing or welding bone insuch fluid circumstances and further where damage to native host tissueis to be avoided.

U.S. Pat. No. 5,498,259, entitled “Method for Fusing Bone” to Mourant,et al. (“Mourant”), is directed to fusing bone by chemically removingthe mineral matrix from a thin layer of the surfaces to be joined andthen heating the joint using electromagnetic radiation. However, theMourant process is conducted in vitro, uses a laser, is not conducted ina fluid medium necessary for in vivo or endoscopic use, and does notachieve weld strengths sufficient for in vivo clinical application.Further deficiencies of Mourant are discussed below.

U.S. Pat. Nos. 5,824,015 and 5,749,895 and 5,669,934, to Sawyer, et al.,describe joining soft tissues, particularly those with lumens such asarteries, utilizing a surface-applied pre-formed film or sheet ofcollagen that is treated with electromagnetic energy. The method ofunion is fundamentally different whereas the substance joining the softtissue acts like an adhesive tape. This process as disclosed does notapply to hard tissues such as bone, due primarily to the uniquestructure of bone and to limited weld strengths demonstrated that areinsufficient for in vivo use.

U.S. Pat. No. 6,033,654, to Stedronsky, et al., describes joining softtissue with a proteinaceous recombinant non-biologic polymer adhesive.Tissue apposition is achieved and held during the healing process. Theinvention is not applicable to bone. The present invention is notdirected to an adhesive, but rather a welding process that creates abiologic “grout” construct that interdigitates with cancellous boneproviding a mechanical construct for fusion/welding and that does notinterfere with healing responses.

U.S. Pat. No. 5,955,514, to Huang, et al., describes a means to joinnon-biologic implants such as metal and ceramic to biologic materialssuch as hard tooth material with non-biologic polymer cement. Thepresent invention does not relate to non-biologic implants such as metalor ceramic but rather to fusing normal tissue to normal tissue, ratherthan fusing bone to metal or ceramic.

U.S. Pat. Nos. 5,885,292 and 5,741,261, to Moskovitz et al., relate tospine surgery rather than endoscopy. Specifically, the means(instrumentation) to achieve a bone fusion is simply providing bonegraft to the spine location with specific tools described.

U.S. Pat. No. 5,788,976, to Bradford, relates to spine surgery ratherthan endoscopy. This is a technique for harvest and preparation of theautologous cancellous bone graft. Bradford harvests the graft andseparates the constituent elements by centrifuging the material and thenuses a portion for treatment. The present invention does not present abone graft harvest method per se but rather treatment of harvested bonegraft. Bradford can make a paste but simply as a delivery method ratherthan as a means to weld. Bradford simply wants to introduce bone graftto an area, limiting harvest sequelae and allowing the benefits of bonegraft to occur at a fusion site. The present invention seeks astructural weld obviating other fixation devices. The autologous graftin the present invention is treated mechanically, chemically, andelectromagnetically.

U.S. Pat. No. 5,584,863, to Rauch, et al., U.S. Pat. No. 5,014,699, toPollack, et al., and U.S. Pat. Nos. 4,266,533, 4,266,532, and 4,105,017,to Ryaby, et al., relate to electrotherapy, a different process thanelectromagnetic energy or radio frequency delivery to tissue duringsurgical or electrosurgical procedures.

U.S. Pat. No. 5,458,596, to Lax, et al., U.S. Pat. No. 6,149,620, toBaker, et al., and U.S. Pat. No. 6,159,194, to Eggers, et al,collectively relate to radio frequency or electromagnetic energydelivery to soft-tissue derived collagen rather than bone-derivedcollagen. Specifically described in these filings are the treatmentand/or contraction of “soft tissue”, “soft tissue collagen”, or “softtissue derived collagen” by applying radio frequency or electromagneticenergy via a conductive medium. The use of these descriptors in thesePatents indicates the distinction between soft tissue-derived andbone-derived collagen further reflecting the non-obvious nature of thepresent invention utilizing radio frequency or electromagnetic energyduring surgical or electrosurgical procedures to treat bone-derivedcollagen or bone-derived material. Further distinctions are discussedbelow.

U.S. Pat. No. 3,982,017, to Thiele, relates to specifically designedinjectable solutions to aid fracture healing. The present inventionutilizes other non-injectable healing aides, such as growth factors,that can be added to the fusing or welding process to augment healing.

U.S. Pat. Nos. 5,516,533 and 5,352,463, to Badylak, et al., relate tosoft tissue derived grafts, not bone-derived grafts.

Laser welding of bone as described by Mourant has provided some optimismthat the Holy Grail of bone fixation can be achieved, i.e., to obtainnormal bone at union sites with no sequelae of fixation devices. In sucha scenario, the resultant bone-bone interface would become a normal boneconstruct after healing. However, results utilizing current techniquesas disclosed in prior art have not been successful in attaining thesegoals, have not been practical in vivo, and, therefore, have not beentransferred to clinical application and patient care.

Bone healing occurs via natural processes when mechanical stability andapposition (i.e. compression) are combined with an adequate host healingresponse. Without both of these mechanical and biologic environments,healing will be impaired. To this end, both components,stability/compression and healing response, can be, and have been,modified, altered, or stimulated by various methods to assist in thehost in vivo healing response. Any fusing or welding process should beattentive to both of these fundamental concerns if such processes are tobe used clinically or conducted in vivo. Bone fusion or welding has beenaccomplished in vitro by delivering electromagnetic energy to the bonesegments that require fixation after acid treatment. However, thedeficiencies of such prior art have obviated use in vivo. The limitedbone fusion/welding strength and duration (including decay) that hasbeen achieved (even with application of specific “solders”), theinability to perform fusion/welding in a fluid (in vivo or duringendoscopy) environment, and the limited applicability of laser energy tocurrent treatment approaches (regulatory and safety issues, licensingand certification requirements, high equipment costs not amenable togeneral clinical practice, and issues of collateral damage during tissueapplication) have reduced the current techniques disclosed in prior artto an in vitro experiment. These techniques do not allow fusion/weldingfixation without other supplementary fixation devices and have not beenapplicable in a fluid and/or in vivo environment.

Provisional fixation techniques are required in orthopedic treatments tohold tissue (bone sections or fragments) in specific positions untiladequate, mature healing responses can be developed by the host organismthat supercedes the requirement of the provisional fixation initiallyutilized. Specific to the techniques of the method of fusing bone asstated in Mourant, “after 16–24 hours of immersion in saline solution,however, the union held less than 500 g before failure”. This strength,and the decay of this strength in a fluid environment, is not adequatefor use in an in vivo environment without additional provisionalfixation techniques and more specifically under endoscopy conditionsthat typically involve a fluid medium. Mourant indicates the need for“external fixation devices [to be] applied to stabilize the bonesegments”. Further, all in vivo healing and cellular processes occur ina fluid medium and are dependant upon tissue hydration (i.e. fluid).These are some of the reasons why the Mourant process has not beenapplied to clinical practices—it does not obviate the need for otherprovisional fixation techniques during the entire healing process andtherefore the application of the Mourant technique is extraneous,possibly dangerous (e.g. acid treatment to host tissue if used in vivo,collateral damage from laser use such as osteonecrosis, etc.), andeconomically burdensome. As disclosed, the procedures serve as “an invitro pre-provisional fixation technique”, not “an in vivo provisionalfixation technique”.

The laser-dye energy direction process as used in Mourant is notamenable in vivo due to the lack of a natural insulator (see disclosurebelow). Tissue such as articular cartilage, fibrocartilage, bone, andligament are adjacent to bone segments, particularly as in jointsencountered during treatment such as endoscopy procedures, and can bedamaged or altered by low level laser energy despite such attempts asdye-solder localization or application mode and technique constraints(B. Fink, et al., “Holmium:YAG laser-induced aseptic bone necrosis ofthe femoral condyle”, Arthroscopy 12:217–223 (1996); D. L. Janzen, etal., “Osteonecrosis after contact neodymium:yttrium aluminum garnetarthroscopic laser menisectomy”, American Journal of Roentgenol169:855–858 (1997); S. R. Rozbruch, et al., “Osteonecrosis of the kneefollowing arthroscopic laser menisectomy”, Arthroscopy 12:245–250(1996); R. Thal, et al., “Delayed articular cartilage slough: two casesresulting from holmium:YAG laser damage to normal articular cartilageand a review of the literature”, Arthroscopy 12:92–94 (1996)). Limitingcollateral damage is critical since it is by the adjacent tissue thatthe natural host healing responses are generated. Electromagnetic energyinduced tissue injury or necrosis impairs both healing responses and thestructural integrity of tissue, negatively affecting both of thefundamental components necessary for bone healing. For these reasons,another source of electromagnetic energy delivery is required for bonefusion/welding in vivo.

The prior art for bone fusion/welding has been labeled “an in vitroexperiment” since the process is performed outside of the host with thesubsequent intentions to re-introduce the segments back into the hostfor further subsequent and traditional fixation. The process involvesacid and electromagnetic energy that is not biocompatible and has raisedmany concerns regarding iatrogenic damage during such processes ifapplied clinically. Maintaining structural and cellular integrity duringsuch procedures is critical due to necessary regulatory clearance andacceptance in peer-reviewed medical circles. It is for these reasons,and others to be disclosed below, that prior art does not provide aconsistent and useful procedure for fusing or welding bone in vivo in afluid medium, such as during endoscopy procedures.

SUMMARY OF THE INVENTION (DISCLOSURE OF THE INVENTION)

The present invention is a method of achieving tissue changes in bone orbone-derived organic tissue comprising providing bone or bone-derivedorganic tissue and applying electromagnetic energy application to thebone or bone-derived organic tissue. In the preferred embodiment radiofrequency energy is applied and the bone or bone-derived organic tissueis in an electrically conductive medium. Further, this invention is amethod of electrosurgical treatment of bone or bone-derived organictissue.

The invention is also of a method of treating bone tissue comprisingproviding bone segments and placing a bioactive interfacing agentbetween the bone segments. In the preferred embodiment, the interfacingagent comprises one or more of osteoconductive, osteoinductive, andosteogenic substances or agents. The interfacing agent preferablycomprises a hydrophobic, lipophilic carrier past-gel-like material andis activated by electromagnetic energy (preferably radio frequencyenergy) and/or heat releasing microspheres.

The invention thus provides a method of achieving tissue changes in boneor bone-derived organic tissue, in which method bone or bone-derivedorganic tissue is provided, an interfacing agent is applied to the boneor bone-derived organic tissue, and electromagnetic energy is applied tothe interfacing agent. The interfacing agent can include collagen,preferably bone-derived collagen, and a therapeutic agent. In a relatedembodiment, a method of treating bone tissue is provided wherein abioactive interfacing agent is placed between the bone segments of thebone tissue to be treated.

A primary object of the present invention is to provide an in vivoprocedure for fusing/welding bone in a fluid medium, such as duringendoscopy. More specifically, the present invention provides a means forperforming in vivo fusing or welding of bone without the need forsupplemental fixation devices. Therefore, an additional primaryadvantage of the present invention is to provide a means to achievesufficient joining strength between bone segments such that supplementalfixation devices are not required during the healing process wherebyeliminating the sequelae of such devices. The process further providesthe primary advantage of the use of a biocompatible interfacing agentthat augments the structural weld strength and contains bioactive agentsthat augment the healing response. Further, the use of electromagneticenergy, and specifically radio frequency, is applied to bone orbone-derived tissue for the first time. This occurs in an electricallyconductive medium with the use of an instrument probe. Both themechanical and biologic environments necessary for bone healing areaddressed and augmented in this invention.

Other objects, advantages and novel features, and further scope ofapplicability of the present invention will be set forth in part in thedetailed description to follow, and in part will become apparent tothose skilled in the art upon examination of the following, or may belearned by practice of the invention. The objects and advantages of theinvention may be realized and attained by means of the instrumentalitiesand combinations particularly pointed out in the appended claims.

DESCRIPTIONS OF THE DRAWINGS

FIG. 1 is an illustration of cancellous and cortical bone comparingmajor structural morphology. Note the gross structural differencesbetween cancellous bone and cortical bone. This fundamental structuraldifference has direct implications for the method of bone welding asdisclosed.

FIG. 2 is a series of electron micrographs depicting the structure ofcancellous bone from various anatomic locations. Note the large numberof bone spicules 210 available for fusion/welding. Note also the largeporous interstices 220 that allow for the interdigitation of thebone-derived composite (biologic interfacing agent) with a significantlylarge surface area per unit of measure when used with the bone spicules.

FIG. 3 graphically illustrates the electromagnetic energy absorptionstructural capacity of bone-derived type-1 collagenous tissue afterremoval of the inorganic component as described in this inventionrelative to electromagnetic energy input. A small range of cross-linkdisruption 310 occurs during a wide range of radio frequency treatment320 of bone-derived type I collagen relative to level of energyapplication. This phenomenon allows maintenance of structural integrityduring radio frequency energy application.

FIG. 4 graphically illustrates the electromagnetic energy absorptionstructural capacity of soft tissue-derived type-1 collagenous tissuerelative to electromagnetic energy input. A large range of cross-linkdisruption 410 occurs during a small range of radio frequency treatment420 of soft tissue-derived type-I collagenous tissue. This phenomenondoes not allow maintenance of structural integrity during radiofrequency energy application.

FIG. 5 graphically illustrates the large range of shrinkage 510 perpercent cross-link disruption 520 that occurs during radio frequencytreatment of bone-derived type I collagen. This phenomenon allowscompression to occur at the spicule level (FIG. 2, 210) of thecancellous bone (FIG. 7).

FIG. 6 graphically illustrates the small range of shrinkage 610 perpercent cross-link disruption 620 that occurs during radio frequencytreatment of soft tissue-derived type-I collagen. This loss ofstructural integrity obviates the ability to utilize soft tissue-derivedcollagenous material for the bone fusion/welding process disclosed.

FIG. 7 illustrates electromagnetic energy application to the compositeas disclosed. Bone segments are locked together much like the analogy ofcement and rebar. When electromagnetic energy 710, such as radiofrequency energy, is applied to this construct, the energy istransmitted preferentially within the bioactive interfacing agentinducing shrinkage and coalescence to itself in a three-dimensionalpattern that locks the porous recipient bone segments together much likethe setting or curing effects of cement or grout reinforced by steelrods or rebar (the cancellous bone spicula and lattice network of therecipient untreated, i.e., undemineralized, bone segments to fuse/weldserves as the “rebar” and the bioactive interfacing agent serves as the“cement” after radio frequency treatment). This figure demonstrates thecomposite weld at the junction of two recipient bone segments. Initialcompression of the segments allows direct apposition and penetration ofthe interfacing agent. The electromagnetic energy induces furthercompression at the spicule level 720 through the bone-derived collagenshrinkage while adding the benefits of bone graft derived osteoinductionand osteoconduction. This process does not interfere with healing,rather it augments healing. Additional bioactive agents 730 are added tothe hydrophobic lipophilic interfacing agent 740.

DESCRIPTION OF THE PREFERRED EMBODIMENTS BEST MODES FOR CARRYING OUT THEINVENTION

The present invention is directed to the in vivo fusing or welding ofbone in a fluid medium. The invention is useful for in vivo proceduresin humans and animals. In particular, the process is useful forendoscopy procedures, e.g., arthroscopy or other joint procedures, butis applicable to all clinical uses because a fluid medium generallyexists during all in vivo conditions and during all healing processes.In such endoscopy procedures, nicks or other openings are made in theskin and a probe and other instruments, devices, or products aredisposed into the body cavity. A camera, or other visualization device,is directed in an opening to view the affected joint, bone, or bodycavity.

Two general types of bone exist in the mature organism and are quitesimilar in all species. Bone is formed based upon the mechanical loadsthat are applied to the tissue at specific locations by the means ofmechanotransduction, i.e., each type is a function of the mechanicalenvironment within which it resides. Cortical bone is the envelope oflong bones or cuboid bones and is mainly subject to bending, torsional,and compressive stresses. Structurally, cortical bone consists of denseor compact layers of lamellar bone and woven bone without open spaces orcavities (i.e. non-porous). Cancellous bone is a porousthree-dimensional lattice network that is mainly subject to compressivestresses. Cortical bone has four times the mass of cancellous bone yetcancellous bone has eight times the rate of metabolic turnover ofcortical bone (cancellous bone is a better source for bone grafting).The porosity of cortical bone is <10% whereas the porosity of cancellousbone is 50–90%. See FIG. 1 and FIG. 2. The inorganic phase of bone iscomposed principally of calcium phosphate mineral; the organic phase ofbone is composed of 90% type I collagen. The material properties of thebone types (energy behavior, strength, energy absorption, ductility,brittleness, viscoelastic behavior, strain rate sensitivity, fatigueproperties, and creep behavior) are affected by many variables and thesevariables can be manipulated for specific treatment purposes. Further,the unique properties and architecture of cancellous bone, i.e. theporosity and the management of compressive stresses, yield a suitablesubstrate for the fusing/welding process as disclosed below.

Bone that is harvested from a patient to be utilized at another site toassist in bone healing, treatment procedures, and reconstruction istermed “autologous bone graft”. Advantages of autologous bone graftinclude no risk of graft rejection, rapid incorporation, augmentation ofhealing, and limited harvest site morbidity. Studies have demonstratedthat cells from autologous bone graft actually are involved in thefusion mass that occurs during the healing process reinforcing thebioactive role of this procedure (S. E. Gould, et al., “Cellularcontribution of bone graft to fusion”, Journal of Orthopaedic Research18:920–927 (2000)). Bone graft that is harvested can be manipulated invitro to then be used in vivo for specific treatments. For example, itcan be mechanically modified such as contouring to fit specific defects,morcellized to mold around treatment sites, or physically compressedinto a smaller area to augment mechanical and structural properties ofthe treatment area. Additionally, bone graft can be chemically modified.Preferably, this would be performed in vitro due to possible damage tonormal host tissue, but may under certain circumstances be performed invivo. For example, acid can remove the mineral component of the bonegraft and a residual portion of the graft would remain devoid of therigidity induced by the mineral component. This residual portion retainsits bioactive properties and can augment bone healing when utilized inan autologous bone graft fashion (M. Zhang, et al. “Effects of thedemineralization process on the osteoinductivity of demineralized bonematrix”, Journal of Periodontol 68(11):1085–1092 (1997)). Further, thismaterial retains its stimulatory properties even after heating whichwill be important in the disclosure below (T. Ito, et al., “Sensitivityof osteoinductive activity of demineralized and defatted rat femur totemperature and duration of heating”, Clin Orthop 316:267–275 July(1995)). This collagen-based residua retains a structural compositionthat is malleable and holds a consistency similar to the nativecancellous bone of origin. Further, this residua is amenable tomodification with electromagnetic energy, such as radio frequencyenergy. Such processes have not been previously described or disclosed.

Radio frequency energy effect upon soft tissue-derived type I collagenhas been well established and the observations continue to grow;however, no data has been previously described for bone-derivedcollagenous material. Generally raising the temperature of softtissue-derived collagen via electromagnetic energy can inducemodifications in its material properties (energy behavior, strength,energy absorption, ductility, brittleness, viscoelastic behavior, strainrate sensitivity, fatigue properties, and creep behavior). The radiofrequency induced behavior of soft tissue-derived type I collagen isaffected by many factors including most notably the constitution of it'sspecific tissue-of-origin (this will be important in the disclosurebelow). For example, tendon, ligament, and joint capsule collagen, whileall soft tissue-derived and primarily type I in nature, demonstratesubstantial response differences to electromagnetic and particularlyradio frequency energy application. These differences not only lie inthe amount of energy that can be absorbed prior to denaturation, butalso in the mechanical and viscoelastic properties thereafter. Ingeneral, during controlled radio frequency energy application, softtissue-derived type I collagen can undergo shrinkage and fibrilcoalescence (M. S. Wall, et al., “Thermal modification of collagen”,Journal of Shoulder and Elbow Surgery 8:339–344 (1999); M. J. Lopez, etal., “Effects of monopolar radio frequency energy on bovine jointcapsular mechanical properties”, Clinical Orthopaedics and RelatedResearch 374:286–297 (2000); and S. S. Chen, et al., “Heat-inducedchanges in the mechanic of a collagenous tissue: Isothermal, isotonicshrinkage”, Journal of Biomech Eng 120:382–388 (1998)). The presentinvention harnesses the novel and heretofore unknown and untried effectsof electromagnetic energy, and specifically radio frequency energy,application upon bone-derived collagen and collagenous material and thebenefits thereof in the bone fusing/welding process disclosed below.

Radio frequency energy delivery can be strongly affected by pH,electrolyte concentration, hydration levels of tissue, and tissueimpedance. Additionally, weaker radio frequency energy deliveryeffectors include collagen organization and tissue senescence.Electromagnetic energy, specifically radio frequency, can induce changesby rapidly oscillating electromagnetic fields that cause movement ofcharged particles within substances and tissue with the resultantmolecular motion, activity, and reaction causing heat. Currenttransmission modes are via ionic or electrolytic solutions and generallyfollow the path of least resistance, a parameter that describes tissueimpedance. Transmission cannot occur to an appreciable level innon-ionic or non-electrolytic environments or in areas with highimpedance to such energy currents. In such non-conducting fluid media,radio frequency energy, for example, is dissipated in electromagneticfield emissions similar to radio waves. In the presence of conductivefluid media, soft tissue is rapidly affected by radio frequency energy.The heat-liable collagen cross-links are disrupted and the materialundergoes transformation from a highly organized crystalline structureto a more random gel-like material. This process has been termed “PhaseTransition” for the collagen derived from soft tissue; changes which arebased upon the tissue-of-origin (P. J. Flory, et al., “Phase transitionsin collagen and gelatin systems”, Journal of the Am Chem Soc80:4836–4845 (1958)).

This process occurs in a different manner with bone-derived collagen,most notably with the resultant material displaying quite differentproperties from that of soft tissue-derived collagen under similartreatment protocols. Controlled application of radio frequency energy tothe residua of cancellous bone graft after removal of themineral-inorganic component (such as with acid treatment) yields asubstance that retains a cohesive network of fibrils that providesstructural strength of a much broader nature that soft tissue derivedcollagen under similar radio frequency treatment protocols. Generally,application of radio frequency energy to soft tissue-derived collageninduces a phase transition including shrinkage and coalescence. Thetissue's structural properties decrease with this treatment (A. L.Wallace, et al., “Electrothermal shrinkage reduces laxity but alterscreep behavior in a lapine ligament model”, Journal of Shoulder andElbow Surgery 10(1):1–6 (2001)) i.e., the soft tissue-derived collagenis less able to withstand tensile loads as well as static and cycliccreep strain. These findings have been quite problematic for clinicaluse since such mechanical environments are typically required during thehealing process in vivo. However, bone-derived collagenous tissue yieldsa material that can support tensile properties to a much greater degreedue to the varied, specific, and unique cross-linking and coalescenceproperties exhibited in the native and treated structure. Although thespecific molecular process have not been clearly elucidated, theseproperties have been shown to be three to four times as large and arefelt to be due to the specific interactions within the native cancellousbone structure prior to harvest and treatment, such as the profile andpattern of bone-derived collagen cross-linking. This phenomenon isgenerally described in terms of those cross-links that are stable orunstable to the effects of electromagnetic energy application. Theunstable cross-links allow denaturation and fibril coalescence while thestable cross-links allow shrinkage that can generate tension.Particularly, the unique bone collagen cross-linking patterns arederived from lysine and hydroxylysine via deamination by lysyl oxidase,which produces an aldehyde amenable to condensation with a lysyl orhydroxylysyl residue of a neighboring collagen molecule. The resultingdivalent aldimine and oxo-imine cross-links are incorporated intrivalent hydroxylysyl-pyridinoline and lysyl-pyridinoline cross-links.The mechanical properties of bone and soft tissue (even within softtissue type) differ substantially even though type I collagenpredominates in each tissue type. Other constitutent factors impartthese differences. The other factors and components that allow for suchdifferences in the material properties before treatment also allow forsuch differences after treatment. These post-radio frequency treatmentmechanical properties of bone-derived collagenous tissue are to beutilized in this bone fusing/welding process.

Electromagnetic energy, and more specifically radio frequency energy,induces disruption of cross-linking between collagen fibers. The degreeto which this cross-linking is disrupted depends upon the nativetissue-of-origin and is a function that describes the disruption ofstructural integrity induced by such energy application. Bone-derivedcollagen responds differently than soft tissue-derived collagen. Theseproperties are displayed in FIGS. 3, 4, 5, and 6. This invention takesadvantage of this newly described phenomenon, not only via the naturalinsulating effects for controlled application (as disclosed below), butalso for the variability between patients and treatment conditions. Thebone-derived tissue contraction that occurs with radio frequencyapplication is able to generate the internal compression (disclosedbelow) that bone healing requires at the bone spicule level while alsoproviding the mechanical stability required. If most cross-links weredisrupted with such treatment, as is often evident with similartreatment upon soft tissue-derived collagen, no tension could bedeveloped within the bone construct and no compression or mechanicalstability could be achieved. This varied disruption of structuralintegrity is a fundamental difference between electromagnetic energy,and specifically radio frequency energy, application upon softtissue-derived and bone-derived collagenous tissue and this disclosurehas been used for the bone fusing/welding process of the presentinvention.

Further, radio frequency energy demonstrates no significant effect uponnative untreated bone with the energy levels utilized clinically incollagen tissue treatment. The pathway for conductivity retains a veryhigh resistance (tissue impedance) when compared to other tissue typesand surrounding fluids. Accordingly, it is, and has been to date,unexpected that radio frequency energy would retain a place in thetreatment of bone tissue. The inorganic phase of bone provides a naturalinsulator against damage to its composition from radio frequency energyand the treatment outlined above occurs only after this phase has beeneliminated. This characteristic is due to the nature and manner by whichthe bound ionic elements reside within the native mineralized bonestructure. This phenomenon allows unaltered bone to serve as a naturalinsulator against collateral damage when utilizing radio frequencyenergy upon bone tissue or adjacent tissue within the parameterstypically utilized. This natural insulation does not occur for examplewith laser application as the photostimulation will occur in normal boneas well as treated bone, limiting its role for clinical use (e.g.iatrogenic osteonecrosis). As this technique can be utilized to controlthe application of radio frequency energy to tissue, and particularly tobone tissue, bone welding is now made possible for the clinician.

Briefly, and to this end, if bone fusion/welding is necessary as part ofthe surgical procedure, a piece of autologous bone is harvested fromanother part of the body. The harvested bone and/or the joint/recipientbone that is being repaired are treated via methods disclosed below. Theharvested bone is preferably treated in vitro and includes the additionof other substances as disclosed below to create an interfacing agentfor the fusion/welding process. The joint or receiving bone, because itremains in the host body, must be treated in vivo. Therefore, simple“de-fat” procedures that are biocompatible have been sufficient for thein vivo recipient bone segments. The harvested bone is provided to theaffected joint or receiving bone and then two recipient bones arefused/welded in vivo using heating methods and technologies such as butnot limited to chemical heating gels, ultrasonic vibration, photonicenergy, etc. Based upon to above disclosure, the current preferredembodiment uses radio frequency electromagnetic radiation. Since theprocedure occurs in vivo, it occurs in a fluid medium, additionallyamenable to endoscopy and electrosurgical procedures.

In the present invention, the harvested bone and/or the recipient bonemay be chemically or mechanically treated to remove or alter the mineralmatrix and provide a good fusion/welding surface. Because thefusing/welding occurs in a fluid medium and in vivo, any chemicalutilized upon the recipient bone in particular must be safe to the humanor animal and to the tissues being treated. In the case of acidpre-treatment of bone surfaces, dilution is necessary. Or, other acidsor chemical compositions, friendly to the host, may be used such asacetic acid, citric acid, malic acid, or other acids found normally inhuman ingested foods or endogenously produced by the host organism.Generally, the harvested bone tissue is treated with demineralizationprocedures as disclosed below; the recipient bone is treated withbiocompatible agents to “de-fat” the porous intersticies, such ashydrogen peroxide, evacuating those spaces to accommodate theintroduction of the bioactive interfacing agent (i.e. the treatharvested bone material) as disclosed below. The additional step ofdemineralization of the recipient bone segments may be required in someinstances to a limited degree and will become apparent to those skilledin the art.

In the present invention, the new and novel configuration of interfaceagent is comprised primarily of a biocompatible acid treatedbone-derived graft material, a carrier substance that allows use in afluid environment, a visualization aid, a substance that channels theelectromagnetic energy, and an osteinductive/osteoconductive compound orcompounds. An example of such a composite would be citric acid, bonegraft, hydroxyapetite, and tricalcium phosphate gel. Such configurationprovides greater stability of manipulation and of placement in an invivo fluid medium such as during endoscopy and addresses all the abovestated concerns of prior art for the bone fusion/welding procedures. Tothose skilled in the art, it is quite apparent that other substances,compounds, or agents may be added as needed for specific treatmentpurposes.

The invention disclosed herein provides a system for bone fusion/weldingthat utilizes a new set of techniques and biomaterials for safety,biocompatibility, controllability, and healing enhancement purposes.This system encompasses six primary components with particular attentionto the preferred embodiment of radio frequency energy application.However, it will be apparent to those skilled in the art that othernuances or variations may apply for other energy sources. First, avisualization aid is required to assist in locating the anatomic regionto be treated via endoscopy techniques or via the direct visualizationof traditional open procedures. The preferred embodiment utilizes both adye enhancement process and biomaterials that interface between thebones to be fused/welded that are visually self-evident. To accommodatevisualization via standard endoscopy equipment, a new system ofendoscopic lenses would be utilized to accurately visualize the area tobe treated. Second, an agent within the interfacing agent composite,that is more conducive to radio frequency energy than normal surroundingor untreated tissue or fluids would effectively channel theelectromagnetic energy to the fusion/weld site while protecting thenormal or untreated tissue or fluids while facilitating thefusion/welding and healing process. This would take advantage of thecontrollability of radio frequency delivery mechanisms as discussedabove and enable a lower energy fusion/welding process more amenable toin vivo applications. This would prevent unintended application of thetreatment to normal and unaffected tissue and add additional safety.Third, interfacing agent enhancing materials are comprised ofhydrophobic and lipophilic biocompatible components to allow applicationin a fluid medium since the fluid or the fusion/welding process couldgenerally distribute the substance(s) into unwanted regions or areas.Fourth, interfacing agent enhancement materials also include weakbiocompatible acid(s) agent(s) to pre-treat the bone surfaces that areto be united utilizing the electromagnetic energy. This process whenused upon the recipient bones creates the thin layer of treatment of theapposed surfaces to facilitate fusion/welding processes. This processwhen used upon the harvested bone material exposes the organic componentto the affects of electromagnetic energy. Fifth, the interfacing agentwould typically include additional bioactive agents that would promotebone healing at the site of fusion/welding in addition to the actualfusion/welding process itself. Examples include but are not limited totricalcium phosphate, hydroxyapetite, or other similar osteoinductive,osteoconductive, or osteogenic compounds, whether naturally occurring,synthetic, or recombinantly produced. Sixth, the by-products of thewelding process, if any, will need to be eliminated or disposed withspecial instrumentation (disclosed below). These techniques should beamenable to in vivo conditions and compatible with the goals of thistreatment, specifically to provide provisional fixation that does notrequire supplemental fixation devices during the healing process withoutinterfering with the natural healing process in a detrimental fashionbut in fact to augment the healing process. It should be apparent to oneskilled in the art that all of these attributes can be in one singledevice or a series of complimentary devices, applied in one step or as aseries of steps. The attributes of the interfacing agent may be in theform of a solder, gel, or paste, or other biomaterials such as but notlimited to a biomaterial wrap, sponge, putty, glue, wedges, shims, mesh,or adhesive products that would be placed around or adjacent to thebone.

The fusing/welding procedure is preferably accomplished by heating bonesegments or other joined bones using radio frequency energy. However, itshould be obvious to those skilled in the art that electromagneticenergy across the entire spectrum from ultraviolet to infrared isappropriate if tuned to the correct energy density. As discussed aboveand based upon the above disclosure, the portion of electromagneticspectrum that is preferred in this application is the region termedradio frequency. Radio frequency energy induces tissue heating bymolecular friction, resistive, and/or conductive heating, or other meanswhereas laser energy induces photostimulation of cellular matter thatgenerates heat. The method and type of energy delivered to thefusion/weld site will generate specific nuances in the methods forfusing bone and particularly in the biosubstances used to interface theapposed bones. In the instance of some radio frequency deliverymechanisms, the energy is applied to tissues through a path of leastresistance; that is penetration of heat is a function the tissueimpedance to such energy currents. This phenomenon can be exploited bythe addition of conducive radio frequency agents as described above tofacilitate the heating process and promoting safety. Additionally, thesource of radio frequency equipment will include a generator thatdelivers radio frequency energy at controlled levels and applicationtimes. The energy is applied to tissue surfaces with the use of aninstrument probe whose composition induces specific current fieldgeometries. This probe may provide application either via local directtissue contact, local indirect non-tissue contact, or via antennaetransmission to a location specified away from the probe tip. The energycan be delivered via multiple modes including but not limited to eithera monopolar or bipolar fashion. Further, the specific fluid medium inwhich the fusion/welding process can occur may be changed in series toaddress each step of the process as disclosed. Generally, a probe tipconfiguration must accurately treat the area and dispose of thenecessary by-products, if any, of the fusion/welding process. Suchinstrumentation provides for evacuation of the immediately surroundingfluid near the fusion/welding site. Additionally, electrodeconfigurations are such that electromagnetic energy is “broadcast” overthe entire fusion site bathing the overall site in low-densityelectromagnetic field energy. Secondary probe configurations provide formore concentrated localized flux fields that treat highly specific areasto promote final fixation through higher levels of heating to thespecific treatment zone.

Furthermore, in this method of fusing/welding bone under in vivoconditions, and specifically under endoscopic conditions, a defect orfracture that is either created via injury or disease, or via iatrogenicmeans in the normal course of a specific orthopedic procedure, iscontoured to a specified shape and fitted with the bone to which it isto be joined much like the pieces of a puzzle (for example, a cylinderhole-tunnel with a cylinder bone plug compressed into the hole-tunnel ora key hole design). This one-to-one fit allows direct apposition of thebone surfaces to be fused/welded and has the additional benefit ofresisting the normal physiologic forces to which the fusion areas aretypically initially subject. The two bones to be joined are preferablyheld together with external pressure or are “pressure-fit” during thefusion/welding process. A compression fit is generated by the bonetissue itself as it is introduced into place with special impacting anddelivery instrumentation. The bioactive interfacing substance can assistthe compression fit by being configured to swell in the presence offluids or in the heating process. This compression fit can be augmentedby other temporary traditional provisional fixation techniques, ifrequired, such as interference screws, wedges, biodegradable devices,shims, etc. until the weld is complete and then would subsequently beremoved at the completion of the procedure. These swelling and fixationcomponents may be combined into the above-described bioactiveinterfacing agent as a single device or used as complementary devices.Additional bone graft or biomaterial could then be placed into the smalldefect that has been created by the temporary provisional fixationdevice as described here and another application of the weldingtechniques can be performed thereafter.

Based upon the above considerations and in a further descriptiveextension of the embodiments, the present invention utilizes autologousbone graft, preferably cancellous in nature but may in somecircumstances contain cortical or other autologous bone structures, thatis harvested from a patient to be utilized at another site to assist inbone healing, treatment procedures, and reconstructions that requirebone fusing/welding. The autologous bone graft is chemically treated asdescribed above to remove the mineral inorganic component of harvestedbone while retaining the integrity of the organic component and itsbioactive and electromagnetic energy response properties. Typicallyconcentrations between 10% and 25% muriatic (HCl) acid are utilized for2 to 10 seconds followed by washing with normal saline to remove theacid (the concentration and the type of chemical treatment can vary asnecessary to remove the inorganic phase/mineral component of specificbone harvest origins). Hydrogen peroxide may additionally be used for“de-fatting” the harvested bone. Typically 3% hydrogen peroxide solutionallows the necessary de-fatting and remains biocompatible. Otherdecalcification techniques, such as microwave decalcification, EDTA,silver, or other types of acid treatments or sequences of treatments,known to those skilled in the art will become readily apparent as othermeans to obtain the organic bone-derived tissue that is amenable toradio frequency energy treatment. Further, the addition of compounds orgrowth factors to this post-treated autologous bone graft material, suchas but not limited to hydroxyapetite, osteogenic protein, hormones-likesubstances, insulin-like growth factors, prostaglandins, chemicalmediators, cellular chemotactic substances, transvection vehicles, andother factors to control gene expression, within this bone-derivedsubstance that would promote, stimulate, or induce various healingproperties via osteoconductive, osteoinductive, or other methods. Suchsubstances may also be activated by the particular electromagneticenergy source used in the fusion/welding process, such as release fromheat-activated microspheres. This complex is additionally combined witha hydrophobic, lipophilic carrier paste-gel-like substance that allowsuse in a fluid environment. This paste-gel is composed of an ionicsubstrate that transmits radio frequency energy via its electrolyticproperties and is composed specifically for the particular area oftreatment and mode of radio frequency use. Materials such as sodiumchloride, potassium chloride, or similar ion-liberating based solutions,compounds, or substances are acceptable media and can be combined withspecific paste-gel-like carriers. The substrate may exceed the ionic andelectrolytic concentration of surrounding tissue and fluid allowingradio frequency energy transmission to be preferential to the substrateand away from normal tissue and surrounding fluids further limiting thepotential for collateral damage and unwanted energy application (inaddition to the natural insulating effects of natural bone to radiofrequency energy), i.e., the path of least resistance or impedance.Additionally, a visualization aid, additive, or dye is included asdisclosed above.

This bioactive material as disclosed can then be used as an interfacingagent during bone welding procedures. This new combination of abiocompatible and bioactive components in the interfacing agentdemonstrates several benefits during the fusing/welding process asdisclosed: 1) directing or channeling the radio frequency energy to thetreatment site; 2) utilizing natural untreated bone as an insulatoragainst untoward effects of excess radio frequency energy application;3) augmenting the healing process due to the residual bioactivecomponents in the material; 4) being amenable to fluid environments(unlike prior art where other agents are water soluble); and 5)participation in the fusion/weld strength providing structural stabilityand compression between the recipient bone segments as a result ofelectromagnetic energy application. These attributes follow thefundamental structural and biologic environments necessary for bonehealing as described above.

This bioactive interfacing agent is impacted into the porosity of thecancellous bone of the two recipient bone segments to be fused. Therecipient bone segments will have been sufficiently prepared in vivo forthis introduction by the above disclosed “de-fat” procedures, and attimes by demineralization. The two segments are then placed togetherunder a compressive load (amenable for cancellous bone), forcing thebioactive interfacing agent further into the porous interstices of therecipient bone segments. The penetration of the bioactive interfacingagent into the recipient bone porous intersticies is critical to thestructural fusion/welding process. At least 2–3 millimeters ofpenetration into normal “de-fatted” recipient bone segments has beendeemed appropriate at each surface of the recipient bone segments. Thispenetration allows the structural integrity of the mineralized bonespicules to serves as rebar (see disclosure below). To those skilled inthe art, it will become apparent that variations in such penetrationwould exist for specific local and anatomic circumstances. As describedabove, the recipient bone segments may be a defect that is eithercreated via injury or via iatrogenic means in the normal course ofspecific orthopedic procedures or bone that is contoured to a specifiedshape and fitted with the bone to be welded much like the pieces of apuzzle (for example, a cylinder hole-tunnel with a cylinder bone plugcompressed in to the hole or a key hole design). This one-to-one fitallows direct apposition of the bone surfaces to be fused/welded. Acompression fit is generated by the recipient bone tissue itself and bythe interfacing agent as it is introduced into place with specialimpacting and delivery instrumentation. When radio frequency energy isapplied to this construct in vivo, the energy is transmittedpreferentially within the bioactive interfacing agent inducing shrinkageand coalescence to itself in a three-dimensional pattern that locks theporous bone segments of the recipient bones together much like thebonding effects of cement or grout reinforced by steel rods or rebar asthe cement or gout cures: the cancellous bone spicula and latticenetwork of the normal “de-fatted” recipient bone segments to fuse/weldserves as the “rebar” and the bioactive interfacing agent, i.e.harvested bone-derived tissue that has been treated to remove themineral component and impacted into the recipient bone porousintersticies of the “de-fatted” recipient bone, serves as the “cement”after radio frequency energy treatment. See FIG. 7. This interfacingagent during phase transition has become a biologic cement between bonesegments that retains biologic bone healing inductive properties. As itcontracts, coalesces, and/or shrinks to itself, it further inducescompression at the interface of the recipient bone segments to befused/welded. The radio frequency energy does not significantly affectthe recipient bone segments to be fused/welded since the mineralcomponent has not been removed and is thus shielded from the energyeffects at the energy levels required. The shrinkage of the bioactiveinterfacing agent and its composition (namely the harvested bone-derivedcollagen) causes contraction and develops tension between segments ofharvested bone-derived collagenous tissue within itself and thereforethis tension is transferred into compression between the recipient bonesegments to be welded due to the inter-locking of the “defatted”cancellous portions of the recipient bone segments to the bioactiveinterfacing agent's contractile nature after electromagnetic energyapplication. This coalescence creates a single structural unit of thebioactive interfacing agent that induces the weld strength. Thisphenomenon is possible due to the unique material property response ofbone-derived collagenous tissue to radio frequency energy disclosedabove. The surface area per cross-sectional area for this weld is verylarge due to the cancellous porous interstices of the recipient bonesegments, and combined with the above considerations of the radiofrequency induced changes of bone-derived collagenous tissue of theinterfacing agent, the welding strengths are much higher than with thecortical fusing/welding techniques described in prior art. No decay isevident in the fusion/weld since the strength is an inherent constructbetween the bioactive interfacing agent and the bone segments that hasbeen formed within and between the compressed bone segments that retainsstructural properties that does not rely upon a single cortical weldsurface. In fact, some swelling occurs during the initial normal healingresponse phase which increases the fusion/weld strength by furtheraugmenting compression at the fusion/weld site of the recipient bonesegments. The recipient bone segment-recipient bone segment interfaceallows a natural healing response due to the apposition of theirsurfaces in a compression mode without hindering biologic processes. Therecipient bone segment-bioactive interfacing agent interface allowsjoining or union and the development of tension within and between thecancellous lattice networks at the spicule level of the recipient bonesegments (the rebar in the cement). Combined, this process induces bonefusing/welding in a fluid (in vivo) environment that creates adequatestrength during the natural healing process of bone without disruptingbut further augmenting the healing response. This process follows thefundamental mechanical and biologic environments required for bonehealing.

Objects and Advantages

Generally, provisional fixation techniques are required in orthopedictreatments to hold tissue (bone sections or fragments) in specificpositions until adequate, mature healing responses can be developed bythe organism that supercedes the requirement of the provisional fixationinitially utilized. The present invention allows bone fusing/welding tobecome the preferred method of in vivo provisional fixation by providinga means for improved fusion/weld strength and simultaneously allowing adecrease in the requirement of traditional provisional fixationtechniques during the treatment procedures. In this manner, the sequelaefrom the use of such traditional provisional fixation techniques (metalor biologic screws, plates, pins, wires, allograft, etc.) can bedecreased and/or eliminated which provides a distinct treatment benefit.Problems such as residual bone defect, exorbitant inflammatoryresponses, infection, and host rejection are some of the more commonproblems associated clinically with current provisional fixationdevices. The current invention discloses for the first time a true “invivo provisional fixation technique” that addresses and reconciles bothof the fundamental environments required for bone healing (mechanicaland biologic).

In vivo bone welding will likely become the preferred method ofprovisional fixation allowing a decrease in the requirement oftraditional provision fixation techniques during the treatment process.The utility of the bioactive interfacing agents combined with highlyspecific electromagnetic energy means enables the routine use of in vivobone fusion/welding as a primary mode of fixation for bone segments,both in fracture care and in reconstruction. This includes specifictechniques such as biologic fixation of the bone-to-bone interface suchas in fracture care, but also in soft tissue-to-bone interface, andother instances like suture anchors or other modes of fixation (such asbut not limited to rivets, tacks, staples, screws, shims, etc.) that canbe made or contoured from bone material and then welded to other bonesegments during specific treatment procedures to provide fixation.Additionally, in situ bone fragments can be fused/welded in vivo toaccomplish specific treatment goals by intra-operative manipulation ofthe bone fragments into appropriate position and followed by bonefusing/welding obviating the requirement for additional provisionalfixation techniques necessary to withstand physiologic loads thatnecessarily occur during the healing process.

A principle object of the invention is a system of in vivo bonefusing/welding that is amenable to the clinical setting. The currentinvention allows bone segments to be welded in a “flowing” fluid mediumutilizing radio frequency energy combined with a bioactive interfacingagent rather than laser and “solders” disclosed in prior art.Configuration of the bioactive agent to be specifically manipulable inthe in vivo joint space and retain its effective boundary in a flowingfluid environment provided the link to clinical application and patientcare. A fluid medium is important since all biologic processes in vivoincluding healing occur in a fluid environment. Even further, thecurrent invention addresses the missing component of prior art iffusing/welding of bone is to be used during the fluid flow encounteredin endoscopy. Most joint reconstruction procedures involves placement ofbone, bioactive agents, devices, and instrumentation in proximity ofadjacent articular surfaces, synovium, ligaments, and/or or cartilageattachments. Endoscopy procedures are currently popular due to the lowermorbidity, quicker recovery, and lower cost of traditional openprocedures. Radio frequency energy is preferred due to its ease ofapplicability in a fluid environment, affordable market cost and highmarket equipment availability, lower collateral damage than withtraditional laser, safety to operating personnel and patients, andcontrollability during application. Further, widespread acceptance inclinical practice has been achieved and FDA clearance has been grantedfor various indications and has led this energy source to dominateclinical practice over the use of other energy sources. A bioactiveinterfacing agent is required in this setting to increase the weldstrength, weld duration, healing rate, and obviate the need for otherprovisional fixation techniques that retain sequelae. Radio frequencyenergy and the bioactive interfacing agent as disclosed are uniquelysuited for this new in vivo bone fusing/welding process.

Further, electromagnetic energy can damage surrounding normal tissue ifnot applied in a carefully controlled and limited fashion. In theclinical setting, patient care procedures cannot utilize such energy ifsignificant collateral damage occurs as a procedure sequelae. Laserenergy as a form of electromagnetic energy can be directed to the areaof application by utilizing a specific light absorbing dye placed at theapplication site to aid in limiting collateral damage. This interactionis dependent upon the wavelength of the laser energy where specific dyeschannel specific laser energy to induce photostimulation of tissue thatinduces heat. This technique provides a means to localize the energynecessary for the specific treatment purposes. Unfortunately, waterabsorbs laser light energy as well and since biologic tissues arecomposed mainly of water, difficulty in preventing collateral damageexists with laser energy despite attempts at localization with lightabsorbing dyes. During endoscopy procedures, the treatment area isfilled with fluid and often continually renewed (flow) that also wouldabsorb energy. Other factors can be manipulated to decrease lasercollateral damage such as altering the power density, spot size, andapplication mode and time. These techniques however rely upon grosstissue examination to determine effects without a natural means ofavoiding collateral damage. The present invention provides a bioactiveinterfacing agent that acts to channel the electromagnetic energy to theagent itself and at the same time benefiting from the natural insulatingaffects of radio frequency energy upon untreated bone, thereby minimizecollateral tissue damage.

To reiterate, the present invention solves certain problems with priorart in addition to the distinction between the previous prior art invitro procedures and the current in vivo procedures as disclosed, asfollows:

Solder versus biologic interfacing agent. Prior art indicates that“there does not appear to be a distinct advantage to using the . . .paste [solder] procedure” (U.S. Pat. No. 5,498,259). This is easilyunderstood in reviewing such soldering techniques. The soldering pasteprocess is not materially involved in the welding and fixation processand does not induce structural or mechanical rigidity itself (like thecement and rebar analogy above). In this manner, these solderingtechniques have been used solely to direct the laser electromagneticenergy to the bone fusion/weld site. Put simply, the paste or solder isan attempt to localize and direct the laser energy. The tissue is heatedto create a fusion/weld in the area of the dye relying upon the heatedbone segments themselves to fuse rather than relying upon theinterfacing agent to become the fusion agent until natural healingoccurs.

Water-soluble paste. Prior art has disclosed a paste that is watersoluble (albumin or water based) and not amenable to use in vivo in afluid or fluid-flow environment. Prior art is “an in vitro experiment”that describes “an in vitro pre-provisional fixation technique”.

Type of bone welded. Prior art has disclosed a sub-optimal “corticalspot-welding process” rather than a “cancellous continuous-weldingprocess” as described in the present invention. The advantage of thecurrent invention is the creation of a higher surface area offused/welded cancellous bone, which creates higher fusion/weldingstrengths per unit area, eliminating the strength decay with timeobserved in prior art.

Although the invention has been described in detail with particularreference to these preferred embodiments, other embodiments can achievethe same results. Variations and modifications of the present inventionwill be obvious to those skilled in the art and it is intended to coverin the appended claims all such modifications and equivalents. Theentire disclosures of all references, applications, patents, andpublications cited above are hereby incorporated by reference.

1. A method of achieving tissue changes in bone or bone-derived organictissue comprising the steps of: providing bone or bone-derived organictissue in an electrically conductive medium; applying an interfacingagent to the bone or bone-derived organic tissue; and applyingelectromagnetic energy to the interfacing agent while the bone orbone-derived organic tissue is in the electrically conductive medium. 2.The method of claim 1 wherein the applying step comprises applying radiofrequency energy.
 3. The method of claim 1 wherein the interfacing agentcomprises collagen and a therapeutic agent.
 4. The method of claim 3,wherein the collagen is bone-derived collagen.
 5. The method of claim 4,wherein the source of bone-derived collagen is acid treated bone-derivedgraft material.
 6. The method of claim 5, wherein the acid treatedbone-derived graft material is derived from autologous bone of thepatient to be treated.
 7. The method of claim 3, wherein the collagen ismade by synthetic or recombinant means.
 8. The method of claim 3,wherein the therapeutic agent comprises hydroxyapetite.
 9. The method ofclaim 3, wherein the therapeutic agent comprises an osteogenic protein.10. The method of claim 3, wherein the therapeutic agent comprises agrowth factor.
 11. The method of claim 1, wherein the interfacing agentcomprises one or more members from the group consisting ofosteoconductive, osteoinductive, and osteogenic substances or agents.12. The method of claim 1, wherein the interfacing agent comprises ahydrophobic, lipophilic carrier paste-gel-like material.
 13. The methodof claim 1, wherein the interfacing agent comprises heat releasingmicrospheres.